Mechanism for acetic acid-catalyzed ester aminolysis

Abstract

This paper reports a computational study elucidating reaction mechanism for amide bond formation from esters and amines catalyzed by acetic acid. Two optional mechanisms (namely, classic stepwise and concerted acyl substitution mechanisms) have been studied. Calculation results establish the reaction energy profiles of both mechanisms and locate all the intermediates and transition states in both catalytic cycles. Our results propose that the concerted acyl substitution mechanism may be more likely wherein the formation of CN bond and the cleavage of CO bond occur concurrently without the need of rehybridization of the carbonyl carbon. This is also consistent with the fact that no significant racemization/epimerization were observed in the amide products when asymmetric esters and/or amines were used as the reactants, because concerted acyl substitution mechanism precludes the intermediacy of tetrahedral adducts and the accompanying generation/elimination of new chiral centers. Further discussion implies that the concerted acyl substitution mechanism may widely occur in related amidation reactions in the presence of different types of coupling reagents.